This invention relates to the compositions and methods for treatment of erectile dysfunction, and more particularly to methods and pharmaceutical compositions for intranavicular administration of vasodilator medicaments to the fossa navicularis of a patient.
The term xe2x80x9cimpotencexe2x80x9d has been used to signify the inability of the male to attain and maintain erection of the penis sufficient to permit satisfactory sexual intercourse. The term xe2x80x9cerectile dysfunctionxe2x80x9d has been suggested as a more precise term xe2x80x9cto signify an inability of the male to achieve an erect penis as part of the overall multifaceted process of male sexual function.xe2x80x9d Droller, M. J. et al. Impotence. Consensus Development Conference Statement, National Institutes of Health (1993).
Erectile dysfunction may result from psychological causes (psychogenic erectile dysfunction) or organic causes or a combination of both. Organic causes include physiological, nervous, vascular and hormonal pathologies or a combination thereof.
The normal physiology of an erection involves nerve impulses that signal certain muscles to relax. These muscles, when contracted, restrict blood flow through arteries in the penis. When relaxed, the muscles permit a significant increase in blood flow. The increased blood flow engorges three groups of erectile tissue within the penis with blood and the penis becomes less flaccid. The engorged erectile tissue and the muscle structure of the penis depress adjacent veins, restricting the flow of blood out of the penis. The restriction of blood flow out of the penis increases and sustains the erection.
Deficiencies of some hormones, such as testosterone, or elevation of others, such as prolactin, can cause erectile dysfunction. Many drugs, such diuretics, antihypertensives, anticonvulsants, narcotics, alcohol, and psychotropic drugs may cause erectile dysfunction as a side effect. Murray, F. T. et al. Amer. J. Medical Sci. 309: 99-109 (1995).
Damage to nerves and blood vessels may also provide an organic cause for erectile dysfunction. Disease processes may involve several aspects. For example, diabetes, which causes damage to both nerves and blood vessels, can cause erectile dysfunction. A significant percent of all diabetic men will suffer from erectile dysfunction.
Methods proposed for the treatment of erectile dysfunction have included external devices, sex therapy, surgical implantation of internal prostheses, injection of drugs directly into the penis and topically applied medications. None of these approaches is entirely effective.
External devices include tourniquets (see U.S. Pat. No. 2,818,855) and externally applied vacuum erection aids. While some clinicians consider externally applied erection aids as a first option for treatment, some patients are unwilling to use such devices. O""Keefe, M., et al. Medical Clinics of North America 79: 415-434 (1995).
Symptomatic sex therapy was originally found to be effective by Masters and Johnson, but later studies have not shown as impressive results. Freudian therapy does not appear to patients to be an attractive alternative. Vickers, M. A., et al. J. Urology 149: 1258-1261 (1993).
Surgically implanted mechanical devices, such as hinged or solid rods and inflatable, spring driven or hydraulic prostheses have been used for some time.
The administration of erection effecting and enhancing drugs is taught in U.S. Pat. No. 4,127,118 to LaTorre. This patent teaches a method of treating male impotence by injecting into the penis an appropriate vasodilator, in particular, an adrenergic blocking agent or a smooth muscle relaxant to effect and enhance an erection.
More recently, U.S. Pat. No. 4,801,587 to Voss et al. teaches the application of an ointment to relieve impotence. The ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and a carrier to assist absorption of the primary agent through the skin. U.S. Pat. No. 5,256,652 to El-Rashidy teaches the use of an aqueous topical composition of a vasodilator such as papaverine together with hydroxypropyl-xcex2-cyclodextrin.
Prostaglandin E1 is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula: 
and is commercially available, e.g., from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under the designation xe2x80x9cAlprostadil USP,xe2x80x9d from Phamacia and Upjohn under the designation xe2x80x9cCaverjectxe2x80x9d and from The Upjohn Company (Kalamazoo, Mich.) under the designation xe2x80x9cProstin VR.xe2x80x9d
Prostaglandin E1 is a vasodilator useful to maintain open blood vessels and therefore, to treat peripheral vascular disease among other ailments. While the potential benefits from transdermal delivery of prostaglandin E1 have long been recognized, prior efforts at developing a topical composition for prostaglandin delivery have not been fully successful.
In one commercially available form (MUSE(copyright), Vivus, Menlo Park Calif.), alprostadil is administered in a pellet deposited in the urethra using an applicator with a hollow stem 3.2 cm in length and 3.5 mm in diameter (Padma-Nathan, H., et al., N. Engl. J. Med., 336: 1-7 (1997), see especially FIG. 1). In the home treatment portion of the Padma-Nathan et al. study, 32.7% of the patients (10.8% of administrations) receiving MUSE(copyright) complained of penile pain and 5.1% experienced minor urethral trauma, compared to 3.3% and 1.0%, respectively, of the patients receiving placebo. Frequency of report of these side effects has varied in subsequent studies: MUSE(copyright) producing penile pain in 17-23.6% of administrations, compared to 1.7% with placebo and minor urethral bleeding reported by 4.8% of patients (Peterson, C. A., et al., J. Urol., 159: 1523-1528 (1998)). In a study on a European population, 31% MUSE(copyright) patients reporting penile pain or burning sensations, 4.8% reporting urethral bleeding, and 2.9% reporting severe testicular pain (Porst, H., Int. J. Impot. Res., 9:187-192 (1997)). The percent of patients responding to MUSE(copyright) treatment, defined as having at least one erection considered sufficient for intercourse, has been reported to be 43% (Porst, 1997), 65.9% (Padma-Nathan et al., 1997) and 70.5% (Peterson et al., 1998), although published editorial comment has suggested that the percent of patients responding in the latter two studies is more properly reported as 30-40% (Benson, G., J. Urol., 159: 1527-1528 (1998).
In particular, there is presently no commercial source for a topical semi-solid formulation that is useful without a supporting device such as a patch, adhesive strip, and the like. For example, U.S. Pat. No. 5,380,760 to Wendel et al. is directed to a topical prostaglandin formulation that includes a pressure-sensitive, adhesive sheet of polyisobutylene.
Working alone, most drugs, prostaglandin formulations included, do not sufficiently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drug formulations typically include a skin penetration enhancer. Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not adversely affect the physical qualities of the available dosage forms (e.g. cream or gel), or the cosmetic quality of the topical composition.
A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Bxc3xcyxc3xcktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997).
A fully successful topical or transmucosal formulation for prostaglandin E1 has not yet been identified and commercially available. Unfortunately, prostaglandin E1 is readily transformed by rearrangement and other reactions. This relative instability tends to complicate efforts at formulating composition for intranavicular delivery.
The present invention addresses these problems by providing a method and compositions for the intranavicular delivery of semi-solid, separation-resistant and chemically stable composition for the relatively rapid, sustained delivery of a vasodilator, preferably prostaglandin E1.
The present invention provides methods and compositions for the treatment of erectile dysfunction by the intranavicular application of pharmaceutical compositions to the mammalian penis.
In another aspect, the present invention provides suitable applicators for the treatment of erectile dysfunction by the intranavicular application of pharmaceutical compositions to the mammalian penis.
The invention provides methods of treating erectile dysfunction comprising the step of placing within the fossa navicularis of the patient an effective erection-inducing amount of a prostaglandin E1 composition of a semi-solid consistency. The composition comprises a vasodilator, preferably prostaglandin E1, a penetration enhancer, a polysaccharide gum, a lipophilic compound, and an acidic buffer system. The penetration enhancer is an alkyl-2-(N-substituted amino)-alkanoate ester, an (N-substituted amino)-alkanol alkanoate, or a mixture of these. The lipophilic compound may be an aliphatic C1 to C8 alcohol, an aliphatic C2 to C30 ester, aliphatic C8 to C30 ester or a mixture of these. The composition includes a buffer system capable of providing a buffered pH value for said composition in the range of about 3 to about 7.4. A preferred pH value is about 3.0 to about 7.4, more preferably about 3.0 to about 6.5, most preferably from about 3.5 to about 6.0.
Intranavicular placement of the vasodilator composition of the present invention, i.e., within in the fossa navicularis, provides a number of advantages over placing such compositions on the skin surface of the penis or depositing a composition within the more proximal xe2x80x9cpars spongiosaxe2x80x9d portion of the urethra. The fossa navicularis is a natural expanded chamber suitably adapted to receive and retain semisolid medicaments. A semi-solid medicament, such as the composition of the present invention, when placed in the fossa has higher impedance to flow at narrowed exits of this space, the meatus and the urethra. The impedance to flow is proportional to the product of the cross sectional area of the path and the path length.
The lining of the fossa navicularis is a non-keratinized stratified squamous epithelium, thereby providing for enhanced permeablility compared to the keratinized epithelium of the surface skin of the outside of the penis.
The use of a short applicator that has a tip that ends within the anatomical limits of the fossa navicularis is less invasive than threading a longer applicator several centimeters up (or proximal) into the penile urethra proper. A suitable applicator is described in U.S. Pat. No. 6,224,573 to Yeager et al., which is incorporated herein by reference to the extent that it is not inconsistent. Preferably, the applicator comprises a reservoir containing an erectionxe2x80x94inducing amount of a semi-solid prostaglandin E1 composition. More preferably, the applicator is a single use device and contains a single dose of the semi-solid prostaglandin E1 composition.
In one embodiment, an amount of the composition of the present invention lacking the active ingredient occupies a position in the applicator between the single dose of the semi-solid prostaglandin E1 composition and the applicator tip. In such an embodiment, the use of the applicator results in a deposit of composition lacking the active ingredient in the proximal fossa navicularis and the distal portion of the penile urethra proper, physically restricting the single dose of the semi-solid prostaglandin E1 composition to the fossa navicularis.
The applicator is typically packed with instructions for use placed on all or some of the following: on the package containing the applicator, in a package insert and on the outside surface of the applicator itself.
The high glycogen content and bacterial flora within the fossa navicularis provides a naturally lower pH within the space, so that lower pH compositions that provide for high solubility of prostaglandin E1 can be more easily tolerated without excessive irritation of the tissues.
The fossa navicularis is also a more immunologically protected site than the adjacent pars spongiosa region of the penile urethra proper. Placing the tip of an applicator within the anatomical limits of the fossa navicularis thus presents less of a risk of circumventing the natural barriers to disease by artificially transporting contaminants, e.g., from the surface of the penis, directly into the penile urethra proper.
A pharmaceutical composition suitable for intranavicular application comprises prostaglandin E1, a penetration enhancer, a polysaccharide gum, a lipophilic compound, and an acidic buffer system. The penetration enhancer is an alkyl-2-(N-substituted amino)-alkanoate ester, an (N-substituted amino)-alkanol alkanoate, or a mixture of these. The lipophilic compound may be an aliphatic C1 to C8 alcohol, an aliphatic C8 to C30 ester, or a mixture of these. The composition includes a buffer system capable of providing a buffered pH value for said composition in the range of about 3 to about 7.4. If desired, stabilizers, preservatives and emulsifiers may be included.
Compositions of the present invention can take the form of a semi-solid suitable for intranavicular application. In use as a intranavicular agent, these compositions exhibit relatively high progtaglandin penetration and bioavailability without requiring a wasteful overloading prostaglandin concentration. The composition further exhibit reduced irritation, sensitivity and damage of local tissues. In a preferred embodiment, the compositions are delivered to the fossa navicularis using an suitable single dose applicator.
Other and further aims, purposes, features, advantages, embodiments and the like will be apparent to those skilled in the art from the present specification and the appended claims.